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Elife. 2017 Dec 18;6. pii: e30498. doi: 10.7554/eLife.30498.

LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair.

Author information

1
Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI, United States.
2
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States.
3
Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, United States.
4
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States.
5
Interdepartmental Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States.

Abstract

Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling molecule broadly expressed by neurons and glia. In adult mice, global inducible (Lrp1flox/flox;CAG-CreER) or oligodendrocyte (OL)-lineage specific ablation (Lrp1flox/flox;Pdgfra-CreER) of Lrp1 attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), Lrp1 is required for cholesterol homeostasis and differentiation into mature OLs. Lrp1-deficient OPC/OLs show a strong increase in the sterol-regulatory element-binding protein-2 yet are unable to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies revealed a decrease in peroxisomal biogenesis factor-2 and fewer peroxisomes in OL processes. Treatment of Lrp1-/- OPCs with cholesterol or activation of peroxisome proliferator-activated receptor-γ with pioglitazone alone is not sufficient to promote differentiation; however, when combined, cholesterol and pioglitazone enhance OPC differentiation into mature OLs. Collectively, our studies reveal a novel role for Lrp1 in peroxisome biogenesis, lipid homeostasis, and OPC differentiation during white matter development and repair.

KEYWORDS:

CNS Myelin Repair; Cholesterol Homeostasis; LRP1; Oligodendrocyte differentiation; Peroxisome Biogenesis; mouse; neuroscience

PMID:
29251594
PMCID:
PMC5752207
DOI:
10.7554/eLife.30498
[Indexed for MEDLINE]
Free PMC Article

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